Objectives To determine the neural and non-neural sources of histamine in the primate brain. ABSTRACT:Histamine is a neuromodulator involved in mediating attention and arousal in the brain. It is also associated with neuropathologies, such as Wernicke's encephalopathy, Alzheimer's Disease, multiple sclerosis, and migraine headaches. Despite its clinical significance, the histamine-system is virtually unstudied in the primate. Thus, we are examining the sources of histamine in the macaque brain by means of neuroanatomical techniques with a monoclonal antibody to histamine. Brain tissue from visual regions of the cerebral cortex, thalamus, and tectum was obtained from the Wisconsin Regional Primate Center, fixed in carbodiimide, cut into 60 um sections, and reacted immunohistochemically for histamine. We find two sources of histamine in the brain. A neural source originates solely from cells in the hypothalamus. These neurons diffusely project their axons throughout the brain. A second histamine source arises from non-neural mast cells, which are found in the neuropil. Both histaminergic axons and mast cells are more numerous in some brain structures than in others, and these differences appear to be related to the role of histamine in normal and pathological functioning. Keywords hypothalamus, tuberomammillary nucleus, mast cells, immunohistochemistry, cortex, thalamus